The objective of this multidisciplinary proposal is to understand key mechanisms of muscle adaptation to exercise in health and, especially, in COPD. Exercise capacity is impaired in COPD, and increasingly skeletal muscle and cardiovascular dysfunction are implicated. Increased oxidative stress and reduced muscle capillarity have been reported and will be a major theme in this application. Studies will be performed in humans with COPD, in mouse muscle single fibers and in several intact transgenic mouse lines to address mechanisms by which hypoxia and oxidative stress affect muscle structure, function and responses to exercise in health and in COPD. In humans, the sources and importance of oxidative stress will be studied in COPD patients with normal and reduced lean body mass (cachectic phenotype). In mice, the possible roles of oxidative stress, inflammation and apoptosis in the exercise response will be investigated using four specially created transgenic lines. Two of these produce an emphysematous phenotype with muscle wasting based on a) inflammation (pulmonary TNF-a overexpression) and b) apoptosis (pulmonary VEGF deletion). The other two deplete VEGF in c) heart and d) skeletal muscle, which is relevant because reduced muscle VEGF levels are found in COPD. Studies will be performed in both isolated single muscle fibers and intact animals. This research program will elucidate the effects of lung damage in COPD on skeletal muscle, and also will address interactions among potential comorbid conditions common in COPD - cardiac and muscle dysfunction. Overarching hypotheses are that while muscle adaptive responses may be in part signaled by oxidative stress, excessive oxidative stress interferes with muscle contractile and vascular function and also the expression of genes important in adaptation, especially VEGF. Project 1 (Wagner) uses muscle biopsy samples from COPD patients studied in Project 3 to assess the roles of inflammation and oxidative stress on muscle function and VEGF expression and action. It also studies the above four transgenic lines to explore possible pathways to muscle dysfunction in COPD and to understand interactions among impaired lungs, skeletal muscle and heart. Project 2 (Hogan) uses mouse single muscle fibers to elucidate the mechanisms by which hypoxia and oxidative stress impair muscle contractile function, using both normal mice and the same transgenic line overexpressing TNF-a in the lung as Project 1. Project 3 (Richardson) examines sources and importance of oxidative stress to acute exercise and to training in patients with COPD. The program is supported by tissue imaging and administrative cores. Elucidating mechanisms of adaptive response to exercise - in particular the role of oxidative stress - and the mechanisms relating lung disease to muscle dysfunction, should lead to specific, rational strategies for improving exercise capacity and quality of life in patients with COPD.